The background description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Hyperuricemia is caused by the overproduction or under-excretion of uric acid, and is considered to be a causative factor of several diseases that significantly impair the quality of life. For example, hyperuricemia is considered the causative factor of gout—the most prevalent form of inflammatory arthritis, characterized by severe pain and tenderness in joints caused by urate crystal accumulation.
Uricosuric agents and xanthine oxidase inhibitors are often prescribed to lower uric acid levels and treat an underlying cause of gout. Xanthine oxidase inhibitors such as allopurinol or febuxostat can reduce the formation of uric acid, and uricosuric agents can inhibit the absorption of uric acid from the kidney back to the blood via the URAT1 transporter.
Benzbromarone is a uricosuric agent and could be an inhibitor of xanthine oxidase, and is known to be highly effective in lowering serum uric acid (sUA). It has been found that therapy using benzbromarone can lead to lowering of sUA even following a single dose and continue to be lowered following multiple doses, and that chronic therapy can bring sUA into target levels of <6 mg/dL. Unfortunately, like many other drugs, benzbromarone is associated with rare cases of hepatotoxicity and acute liver failure. The toxicity of the drug was believed by many to outweigh the benefits, and benzbromarone was reduced to limited use in the European market by its sponsor in 2003.
Several attempts have been made to formulate compounds and pharmaceuticals with high potency, and reduced toxicity, for example in U.S. 2013/0225673 (to Wempe et al.) describes uric acid transport inhibitors that can potentially be applied topically. Unfortunately and in part because the mechanism of damage/toxicity has not been clear, all or almost all prior attempts suffer from several disadvantages. For example, there is no evidence of the reproducibility and effectiveness of topical administration of such compounds.
These and all other extrinsic materials discussed herein are incorporated by reference in their entirety. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
There have been many efforts to stabilize drugs and reduce production of unwanted metabolites. For example, US 2016/0031879 to Karra et al. teaches deuterated indolizine compounds to stabilize drugs for the treatment of multiple sclerosis and Alzheimer's disease. Karra, however, does not appear to teach application of this approach to modified benzbromarone compounds.
Others, for example in US 2015/031768 to Groves et al., have contemplated modifying some carbon containing compounds. However, the taught modifications were directed to labeling such compounds to generate imaging agents for PET applications, and not directed towards reducing toxicity.
Thus, there is still a need in the art for a highly potent gout/hyperuricemia drug with reduced toxicity.